Heterocyclic compounds and means for producing the same



United States Patent 3,485,842 HETEROCYCLIC COMPOUNDS AND MEANS FORPRODUCING THE SAW .lohn Davoll, Broadlands Ave, Shepperton, England NoDrawing. Continuation-impart of application Ser. No. 393,741, Sept. 1,1964. This application June 14, 1966, Ser. No. 557,353 Claims priority,application Great Britain, Sept. 20, 1963 (provisional), Sept. 17, 1964(complete), 37,193 Int. Cl. C07d 51/42 US. Cl. 260256.4 4 ClaimsABSTRACT OF THE DISCLOSURE 2,4-diaminoquinazolines (I) and their acidsalts N I Y X NH:

are prepared: by reducing a 2,4-diamino-fi-nitroquinazoline to thecorresponding 2,4,6-triaminoquanazoline; by reacting an aldehyde ArCHOor ketal Ar-C (alkyl) O-alkyl 2 Summary and detailed description Thisapplication is a continuation-in-part of my copending application Ser.No. 393,741 filed Sept. 1, 1964, now abandoned.

This invention relates to novel chemical compounds and to means ofproducing the same. More particularly, the invention relates to2,4-diaminoquinazolines having in free base form the formula:

I l N X l lHz (I) and acid addition salts thereof, Where A representsthe group NH Ar-CH N; or

ArCH-N- it. i.

X is a hydrogen or chlorine atom or a methyl group; R and R representhydrogen or lower alkyl (especially C alkyl); and Ar signifies a phenylgroup; a substituted phenyl group such as a mono-, dior tri-(loweralkyl) phenyl, monoor di-(halo)phenyl, hydroxyphenyl, monodior tri-(lower alkoxy)phenyl, carboxyphenyl, carb-(lower alkoxy)phenyl,nitrophenyl, aminophenyl, monoor di- (lower alkyl)aminophenyl, oracetaminophenyl group; a naphthyl group; a substituted naphthyl groupsuch as a halonaphthyl, hydroxynaphthyl, nitronaphthyl, aminonaphthyl orlower alkoxynaphthyl group; or a heterocyclic group such as a furyl,thienyl or pyridyl group.

In accordance with the invention, novel 2,4,6-triaminoquinazolines(Formula I above where A is an amino group and X has the above-specifiedsignificance) are prepared by subjecting the corresponding 2,4-diamino-6-nitroquinazoline free base or acid addition salt to reduction. Thereduction can be carried out in several different Ways. For example, itcan be carried out with stannous salts in mineral or organic acid (suchas acetic or hydrochloric acid) followed by base decomposition of theresulting complex; with hydrogen gas and a metal hydrogenation catalyst;or with similar reducing means. A preferred reagent is stannous chloridein hydrochloric acid. The reaction conditions are subject toconsiderable variation. In the case of stannous chloride, at least threemoles and preferably a slight excess are used for each mole ofnitroquinazoline, but larger excesses can be employed if desired. Thereaction proceeds at ordinary temperature, preferably in the range fromabout 0 to 30 C., and is ordinarily complete in a short period, i.e.,about 1 to 10 hours. Following reaction, the mixture is decomposed byaddition of base such as aqueous sodium hydroxide and the product isisolated as the free base or after acidification as the acid additionsalt.

For the hydrogenation by catalytic means, a variety of conditions andcatalysts can be used. Hydrogen pressures ranging from atmospheric toabout atmospheres are suitable, although relatively low pressures of theorder of about 5 atmospheres are preferred. Moderate temperatures, i.e.,temperatures in the range of about 25 to 100 C., are ordinarilyemployed. While palladium is a preferred catalyst for the hydrogenation.Raney nickel and noble metal catalysts such as platinum, palladium oxideand platinum oxide can also be used. The hydrogenation is carried out inan inert organic solvent such as dimethylformamide or ethanol.

According to a further embodiment of the invention, substituted aminocompounds of formula:

N Ar-C=N X NH: (III) to reduction; Where X, R, and Ar have theabove-specified significance. The reaction with the carbonyl compoundcan be run under a variety of conditions. Various organic solvents ormixtures thereof can be used, e.g., lower alkanols, hydrocarbons, cyclicethers such as tetrahydrofuran, and dioxane, 2-ethoxyethanol,dimethylformamide and aliphatic ethers. The reaction is usually run atreflux temperature in the range from about 35 to 150 C. and preferablyfrom about 60 to C. At these temperatures the reaction is ordinarilycomplete in one-half to ten hours or in about one to four hours at thepreferred temperature range. For purposes of the invention the imineproduct obtained (Formula HI) need not be isolated and can be useddirectly for the reduction. The reduction can be carried out in variousWays, for example, by means of hydrogen gas and a metal hydrogenationcatalyst, by reaction with an alkali metal borohydride or by othersimilar means. The hydrogenation is carried out in a solvent such asethanol, dimethylformamide, tetrahydrofuran, acetic acid, toluene,benzene or mixtures thereof, or in a Water-miscible solvent such asethanol or Z-ethoxyethanol optionally in admixture with water. Ashydrogenation catalysts, one may use Raney nickel, Raney cobalt or thelike, or a noble metal catalyst such as palladium, platinum, oxidesthereof and similar catalysts. With a nickel or cobalt catalyst,hydrogen pressure of about 30 to 100, and preferably 50 to 70,atmospheres are used; and the reduction is suitably carried out attemperatures in the range of about 50 to 120 C., a range of 80 to 110 C.being preferred. With a noble metal catalyst, a hydrogen pressure ofabout one to three atmospheres is used, the reduction being carried outat room temperature or, if desired, at higher temperature up to about 60C. Reduction with an alkali metal hydride (e.g., sodium borohydride) iscarried out in an organic solvent such as a lower alkanol, ether,tetrahydrofuran and the like, at temperatures in the range from about 20to 20 C. and preferably in the range from to C., using at least one moleof the hydride for each mole of imine compound. The method is forreduction of compounds having substituents which are to be maintainedintact such as a nitro substituent.

According to a still further embodiment of the invention the substitutedamino compounds of Formula II where R is lower alkyl are produced byreacting the corresponding substituted amino compounds of the sameformula where R is hydrogen, with an N-alkylating agent such as an alkylhalide, sulfate or sulfonate. The reaction is preferably carried out inan inert organic solvent such as ethanol or dimethylformamide. Therelative proportions of reactants can be varied widely but it ispreferred to use a slight excess of the alkylating agent. The reactiontemperature is not critical but temperatures in the range from 40 to 150C. are preferred.

The free base compounds of the invention form acid addition salts uponreaction with organic and inorganic acids. Some examples of the acidaddition salts of the invention are the inorganic acid salts such as thehydrochloride, hydrobromide, hydroiodide, sulfate and phosphate andorganic acid salts such as the carbonate, succinate, benzoate, acetate,citrate, malate, maleate, p-toluenesulfonate, gluconate, ascorbate,benzene-sulfonate and sulfamate, as well as salts with fluorescein anddibasic acids such as methylenebis(hydroxynaphthoic acid). The acidaddition salts are conveniently formed by mixing the free base with atleast an equivalent amount of the acid of the acid in a solvent in whichthe salt is insoluble, particularly after chilling, thereby permittingrecovery of the desired salt as a solid phase. The inventioncontemplates the acid salts broadly. Those salts which are unsuited toparticular uses as for example uses where toxicity is a problem, arenevertheless useful as intermediates, being readily convertible tonon-toxic acid salts by means which per so are known to those in theart. Whereas both the free base and salt forms of the products areuseful for the purposes of the invention, the salts of the triamine andsubstituted amino products (where A of Formula I is NH and are generallypreferred in those cases where increased stability and water solubilityare desired.

The products of the invention possess significant pharmacologicalproperties as shown in standard tests. In particular, the S-substituted2,4,6-triaminoquinazolines (Formula I where A is NH and X is chloro ormethyl) possess antibacterial activity.5-chloro-2,4,6-triaminoquinazoline and its salts, for instance, areactive in vitro against tuberculosis, Streptococcus, Proteus,Pseudomonas and Salmonella organisms, being active also againstbacterial infection in the mouse. Significantly, the latter productspossess a synergistic action with sulfonamide antibacterial agentsagainst infection caused by gramnegative organisms.2,4,6-triaminoquinazoline (Formula I where A is NH and X is hydrogen)possesses both antiviral activity and diuretic activity. The iminecompounds of Formula III have antiviral, diuretic and/or antibacterialactivity. The substituted amino compounds of Formula II in generalexhibit antiparasitic, anthelmintic, anitiviral, antibacterial, anddiuretic activity. More particularly, the substituted amino compounds ingeneral posses a unique mode of action against certain malarialparasites which are resistant to pyrimethamine, chloroguanide, acridinesand the like. Also, some of the latter compounds show activity againstChagas disease (Trypanosoma cruzi infection) and are effective againstpinworms and the causative agents of amebiasis (E. histolytica) andtrichomoniasis (T. vaginalis). Accordingly, as the free base or acidaddition salt in appropriate pharmaceutical dosage form, the2,4,6-triaminoquinaz0line compounds of the invention have application asantibacterial agents or antiviral or diuretic agents. The iminecompounds of Formula III are applicable as antiviral, diuretic and/orantibacterial agents and the substituted amino compounds of Formula IIas antiparasitic, anthelmintic, antiviral, antibacterial and/ ordiuretic agents. The products are also useful as intermediates for theproduction of other organic compounds.

It will be appreciated that for clniical use the pharmacologicallyactive compounds of the invention can be made up, in accordance withWell known pharmaceutical techniques, into compositions having as anessential active ingredient a 2,4,6-triaminoquinazoline compound of theFormula I above or an acid addition salt thereof. The compositions willgenerally contain in association with the active ingredient one or morepharmaceutical diluents and/or excipients of the kind normally used inthe production of medicaments ready for use. If desired, thecompositions can be made up in :a dosage unit form suitable for theparticular mode of administration, the quantity of active ingredient ineach dosage unit being such that one or more units are required for eachtherapeutic administration. The dosage unit may exist, for example, inthe form of a tablet, pill, sachet, packaged powder or encapsulatedpowder for oral administration or in the form of a sterile injectablesolution or suspension contained in an ampoule for parenteraladministrat1on.

The invention is illustrated by the following examples.

Example 1 (a) 2,4-diamino-6-nitroquinazoline (52.5 g.) is added withcooling and stirring to a solution of stannous chloride dihydrate (190g.) in one liter of concentrated hydrochloric acid while maintaining thetemperature below 30 C. The reaction mixture is stirred for one hour at20 C. and then for two hours at 0 C. whereupon the solid product(stannichloride complex) which has separated is collected, washedsuccessively with concentrated hydrochloric acid and ether, dried anddissolved in hot water (300 ml.). A solution of sodium hydroxide g.) inwater ml.) is added to the hot solution, and upon cooling, the desiredproduct, 2,4,6-triaminoquinazoline, which separates, is collected; M.P.after decolorization with charcoal and recrystallization from water255257 C. The hydrochloride, hydrobromide, sulfate. sulfamate andp-toluenesulfonate salts can be prepared from the free base by treatingan ether solution of the free base with one equivalent of thecorresponding acid.

(b) 2,4-diamino-6-nitroquinazoline (1.03 parts by weight) as asuspension in dimethylformamide (25 parts by volume) is hydrogenated atOrdinary temperature and pressure using 10% palladised charcoal. Afterabsorption of the theoretical amount of hydrogen (30 minutes), thereaction mixture is filtered and the filtrate concentrated to a lowvolume by removal of solvent. The residual product,2,4,6-triaminoquinazoline, is purified by crystallization from water;M.P. 255258 C. The product can also be obtained in good yield by thesame procedure but using higher temperature (100 C.) and pressure (55atmospheres) for the hydrogenation.

The starting material for (a) and (b) above,2,4-diamino-6-nitroquinazoline, can be prepared by nitration of2,4-diaminoquinazoline, according to the following description: asolution of 2,4-diaminoquinazoline (30 g.) in water (900 ml.) is treatedat 95 c. with concentrated nitric acid (60 ml.). After cooling, theresulting nitrate salt is collected, washed with water, and dried. Thenitrate salt (37.2 g.) is added in small portions with stirring to amixture of fuming nitric acid (186 1111., density 1.5) and concentratedsulphuric acid 186 ml.) while maintaining the temperature below 10 C.The mixture is stirred for minutes in the cold and is then allowed towarm up to C. over a one-hour period. The resulting clear solution isadded to ice (2 kg.) and the mixture is adjusted to pH 7-8 by additionof concentrated aqueous ammonia while maintaining the mixture at lowtemperature by addition of ice as necessary. The solid product,2,4-diamino-6-nitroquinazoline, is collected and washed with Water. Theacetate salt is obtained by recrystallization of the product fromglacial acetic acid; M.P. greater, than 350 C.

Example 2 (a) The starting material2,4-diamino-5-chloro-6-nitroquinazoline (22.1 g.) is added below 30 C.to a stirred solution of 65 g. of stannous chloride dihydrate in 350 m1.of concentrated hydrochloric acid and 92 ml. of acetic acid and themixture is stirred 18 hours at 20 C. The resulting precipitate iscollected by filtration, washed with minimum amounts of concentratedhydrochloric acid and water, and then suspended in ice water. The=mixture is basified with 40% aqueous sodium hydroxide while adding iceto maintain the temperature below 40 C. The solid free base product,2,4,6-triamino-5-chloroquinazoline monohydrate, is collected, washedwith water and dried; M.P. 200-203 C. after recrystallization from waterfollowing charcoal treatment. The hydrochloride, hydrobrornide, sulfate,sulfamate and p-toluenesulfonate salts are prepared from the free baseby treating an ether solution of the free base with one equivalent ofthe corresponding acid.

(b) The starting material for (a) above can be prepared from knownmaterials by the following procedure: A mixture of 37 g. of6-chloroanthranilonitrile and 34.3 g. of cyanamide dihydrochloride in240 ml. of diethylene glycol dirnethyl other is stirred and heated at145150 C. for 2.5 hours. The mixture is cooled, diluted with 700 ml. ofether and the precipitated crude product, 2,4-diamino-S-chloroquinazoline hydrochloride, is collected and powdered. The crudeproduct is stirred with 2.5 liters of boiling water; the mixture isbasified with aqueous ammonia,

quinazoline, removed by filtration. After recrystallization from waterthe product melts at 183-185 C. To a stirred mixture of 270 ml. offuming nitric acid (d.=1.5) and 270 ml. of concentrated sulfuric acid isadded portion- Wise over a 2.5 hour period, 50 g. of 2,4-diamino-5-chloroquinazoline, while keeping the temperature below 20 C. Theresulting solution is allowed to stand for 18 hours, then poured onto 3kg. of crushed ice. The mixture is basified with aqueous ammonia(d.=0.880) while adding ice to maintain the temperature below 40 C. Theproduct which separates, 2,4-diamino-5-chloro-6-nitroquinazoline, iscollected, washed with Water and dried.

Example 3 (a) A mixture of 2,4-diamino-5-methyl-6-nitroquinazoline,acetate salt (9.0 g.), 500 ml. of ethanol and 1.0 g. of 10% palladium oncharcoal is shaken with hydrogen at atmospheric pressure and 45 C. untilhydrogen uptake ceases. The mixture is filtered and the filtrateconcentrated to a volume of 50 ml. and chilled to crystallize the freebase product, 2,4,6-triamino-5-methylquinazoline; M.P. 220-222 C. Thehydrochloride, hydrobromide, sulfate, sulfamate and p-toluenesulfonatesalts are prepared from the free base by treating an ether solution ofthe free base with one equivalent of the corresponding acid.

(b) The starting material for (a) above can be prepared by the followingillustrative procedure: 6-chloroo-tolunitrile (60 g.) is added inportions with stirring in the cold (-15 to 10 C.) to fuming nitric acid(300 ml; density, 1.5). The mixture is allowed to stand for 24 hours atroom temperature, and is then added, with stirring, to 4.5 liters of icewater. The solid which separates, 6-chloro-3-nitro-o-tolunitrile, iscollected and recrystallized from aqueous ethanol; M.P. -80 C. A mixtureof 20 g. of the latter product, 38 g. of guanidine carbonate and 1.0liter of 2-ethoxyethanol is heated at reflux for 3.5 hours. The solutionis evaporated at reduced pressure and the residue triturated with 200ml. of water. The crude 2,4-diamino-5-methyl-6-nitroquinazoline iscollected by filtration and dissolved in 200 ml. of hot aqueous aceticacid. The solution is filtered, diluted with 30 ml. of 6 N aqueousammonia and chilled to crystallize the acetate salt of2,4-diamino-5-methyl-6- nitroquinazoline; M.P. 288 C. withdecomposition.

Example 4 2,4,6-triaminoquinazoline (3.5 g.) and benzaldehyde (2.12 g.)are refluxed together in ethanol (40 ml.) for two hours. The reactionmixture is cooled and the resulting product, 2,4-diamino 6benzylideneaminoquinazoline, collected and recrystallized from ethanol;M.P. 222 C.

By the same procedure, other similar condensation products can beprepared starting with proportionate quantities of2,4,6-triaminoquinazoline and the respective aldehyde, as follows:

treated with charcoal and filtered. The hot filtrate is chilled and thecrystalline product, 2,4-diamino-5-chloro- Similarly, the same procedurein which benzaldehyde is replaced with an equivalent amount ofsalicylaldehyde,

7 or mor p-hydroxybenzaldehyde provides as a product the respective a[(2,4 diamino 6 quinazolinyl) imino]-o-, mor p-cresol.

Example 8 Example 8 2,4,6 triaminoquinazoline (5.25 g.) andp-carbethoxybenzaldehyde (5.34 g.) in ethanol (40 m1.) are heated underreflux for 2 hours. After cooling the reaction mixture, the desiredproduct, a[(2,4-diamino-6-quinazolinyl)- imino1-p-toluic acid, ethylester, is collected in solid form and recrystallized from aqueous2-ethoxyethanol; M.P. 248249 C. The free acid is obtained by refluxingthe product (4.13 g.) with 2 N sodium hydroxide (65 ml.) for one-halfhour and acidifying the resulting solution with acetic acid to pH 6. Thefree acid product, OL-[(2,4- diamino-6-quinazolinyl)imino]-ptoluic acid,is collected and purified by dissolution in dilute alkali andreprecipitation with acetic acid.

Example 9 2,4,6-triaminoquinazoline (3.5 g.) and o-nitrobenzaldehyde(3.02 g.) in acetic acid (60 ml.) are refluxed together for 2 hours.After cooling, the solid product which Aldehyde 2,4diamino quinazolineproduct M.P., C.

p-Fluorobenzaldehyde G-(p-fluorobenzylideneamino) 257-259o-Chlorobenzaldehyde 6-(o-chlorobenzylideneamino) 260-261m-Chlorobenzaldehyde 6-(m-chlorobenzylideneamino) 239-2402,4-dichlorobenzaldehydetr(2,4dichlorobenzylideneamino) 259-26 13,4-dichlorobenzaldehyde. 6-(3,4-dich1orobenzylideneamiuo) 2 58 Example6 2,4,6-triaminoquinazoline (3.5 g.) and p-chloro-benzaldehyde (2.81 g.)are refluxed together in 2 ethoxyethanol (40 ml.) for 2 hours. Themixture is cooled and Water ml.) is added, whereupon the product, 2,4-diamino 6 (p-chlorobenzylideneamino)quinazoline, separates, and iscollected; M.P. 280282 C., after recrystallization from 75% ethanol. Ifm-methoxybenzaldehyde is substituted for p-chlorobenzaldehyde in thisprocedure, the resulting product is 2,4diamino-6-(mmethoxybenzylideneamino)quinazoline, M.P. 223-225 C.Likewise, where p-dimethylaminobenzaldehyde (2.98 g.) is substituted forp-chlorobenzaldehyde in this procedure, the product on cooling andaddition of ethanol is 2,4 diamino 6 (p dimethylaminobenzylideneamino)quinazoline; M.P. 288-290 C.; similarly, where one substitutesp-methylaminobenzaldehyde for p-chlorobenzaldehyde, the product is2,4-diamino-6-(p-methylaminobenzylideneamino)quinazoline.

Example 7 A solution of 2,4,6 triaminoquinazoline (7 g.) andanisaldehyde (5.45 g.) in hot dimethylformamide (70 separates,2,4-diamino 6 (o-nitrobenzylidenearninoJ quinazoline acetate, iscollected and recrystallized from water as the hemihydrate; M.P. 220-222C. (dec.).

Example 10 (a) A solution of 15.1 g. of 2,4,6-triaminoquinazoline and12.0 g. of acetophenone in 200 ml. of 2-ethoxyethanol is heated atreflux for 2 hours. The solution is cooled, 200 ml. of ethanol is addedand the mixture is hydrogenated for 2 hours at a temperature of 100- 110C. and hydrogen pressure of about atmospheres using Raney nickelcatalyst. The mixture is cooled, filtered to remove catalyst, andevaporated at reduced pressure to give the product,2,4-diamino-6-[(or-methylbenzyl) amino]quinazoline; M.P. (hemihydrate),200- 202 C. after crystallization from aqueous ethanol. Themonohydrochloride salt is prepared from the free base and one equivalentof hydrochloric acid in aqueous ethanol followed by concentration andcooling.

By the same procedure, other related free base and acid salt productscan be prepared starting with proportionate quantities of2,4,6-triaminoquinazoline and the respective ketone Ar(-R )C O, asfollows:

3,4-Dimethoxyphenyl methyl ketone6-[(3,4-dimethoxy-a-methylbenzyl)-aminol.

p-Hydroxyacetophenone 6-[p-hydroxy-oz-methylbenzyl)amino}.

Example 11 A solution of 16.5 g. of 2,4,6 triamino-S-methylquinazolineand 17.5 g. of 3,4 dichlorobenzaldehyde in 200 ml. of ethanol is heatedat reflux for 2 hours. The mixture is then hydrogenated at 45-50 C. at ahydrogen pressure of 1 atmosphere using 10% palladised charcoalcatalyst. The mixture is cooled, filtered to remove catalyst, andevaporated at reduced pressure to give the free base product, 2,4diamino 6 [(3,4 dichlorobenzyl)amino]-5-methylquinazoline. The free baseis dissolved in ethanol and the solution treated with one equivalent ofhydrochloric acid. On dilution with water and cooling, themonohydrochloride salt monohydrate is obtained; M.P. 287290 C.

the product which separates; 2,4-diamino-6-benzylaminoquinazoline saltwith one-half formula Weight of pamoic acid which crystallizes with onemole of water and onehalf mole of ethanol; M.P. 189-190 C.

Carbonyl compound 2,4-dlamino-5-rnethylquinazo1lne product2,4,S-trimethylbutyrophenone. B enzaldehyde 2-naphthaldehyde2,4-dichlorobenzaldehydeo-C hlorobenzaldehyde Anisaldehyde2-p3n'ldinecarboxaldehyde p-Dimethylaminobenzaldehyde"6-[(m-carbethoxybenzyl) amino Furfural 6-[(2-furfu.rylmethyl) amino].

p-Acetaminobenzaldehyde- 2-hydroxy-l-naphthaldehyde--2-amino-1-naphthaldehyde ylbenzyD-amino]. G-(benzylarnino); M.P., 191195C. G-(Z-naphthyhnethylamino).

6-[(2,4-dich1orobenzyl)amino].

fi-I(p-acetaminobenzylmethybamino].

fi-I(2-hydroxy-l-naphthylmethyl) amino]. 6-[(2amino-1-naphthylmethyl)amino].

2-methoxy-l-naphthaldehyde fi-I(2-methoxy-1-naphthylmethyl)amino].

Example 12 (a) A solution of 2,4-diamino-6-benzylideneaminoquinazolineis prepared by refluxing together 2,4,6-triamino-quinazoline (3.5 partsby Weight), benzaldehyde (2.12 parts by weight) in Z-ethoxyethanol (40parts by volume), for one hour. Ethanol (40 parts by volume) is added tothe cooled solution, and the mixture is hydrogenated for 2 hours at atemperature from 100110 C. and at a hydrogen pressure of about 50atmospheres using Raney nickel catalyst. The mixture is cooled, filteredand concentrated by evaporation to 12.5 parts by volume. Water andethanol and 6.25 parts by volume) are added, and the mixture allowed tostand in the cold. The desired product which separates,2,4-diamino-6-benzylaminoquinazoline, is collected and crystallized from40% ethanol; M.P. 218220 C.

In the same way, other benzylamino compounds can be prepared startingwith the triaminoquinazoline and corresponding aldehydes, as follows:

2,4-diamino quinazoline (b) As an alternative to the procedure ofparagraph (a), a solution of 2,4 diamino 6 benzylideneaminoquinazolineis prepared in the same Way except that ethanol is used in place of2-ethoxyethanol and the solution is refluxed for 2 hours instead of onehour. The solution is then hydrogenated at 45 C. in one atmosphere ofhydrogen gas using 10% palladised charcoal catalyst. Water (40 parts byvolume) is added and the mixture is filtered while boiling, whereuponthe 2,4-diamino-6-benzylaminoquinazoline product separates on cooling;M.P. 217-219 C. The same procedure starting with an equivalent amount ofp-tolualdehyde in place of benzaldehyde provides 2,4- diamino 6(p-methylbenzylamino)quinazoline; M.P. ZOO-201 C.

(c) As a further alternative, a solution of 2,4-diamino-6-benzylideneaminoquinazoline prepared as in paragraph (b) is treatedwith a solution of sodium borohydride (2.28 g.) in ice-cold methanolml.). After one-half hour, the mixture is heated to boiling and allowedto cool. The 2,4-diamino-6-benzylaminoquinazoline sepaartes and iscollected and recrystallized from aqueous ethanol; M.P. 217 C. Thehydrochloride salt is prepared by crystallizing the free base from watercontaining one equivalent of hydrochloric acid; M.P. 298-300 C.Crystallization of the base from water containing 2.2 equivalents offormic acid provides the monoformate salt as a monohydrate; M.P. 208-210C. The salt with pamoic acid [4,4'-methylenebis(3-hydroxy-2-naphthoicacid)] is prepared by dissolving the free base (4.45 g.) and the acid(3.27 g.) in hot 96% ethanol (0.5 liter) and collecting Example 132,4-diamino 6 (2,4,6 trimethylbenzylideneamino)- quinazoline (11.8 g.)in ethanol (200 ml.) is hydrogenated for about two hours under 60atmospheres of hydrogen at a temperature of 110 C. using Raney nickelcatalyst. The mixture is cooled, filtered, the solvent removed byevaporation, and water ml.) added to the residue. The solid product, 2,4diamino 6 (2,4,6-trimethylbenzylamino)-quinazoline is collected andrecrystallized from ethanol; M.P. 248-249 C.

In the same way, other substituted benzylamino compounds can be preparedstarting with the corresponding substituted benzylideneamino compoundswhich in turn can be prepared from the corresponding substitutedbenzaldehydes by condensation with 2,4,6-triarninoquinazoline as inExample 5. The following tabulation illustrates such other substitutedbenzylamino compounds, identified with reference to the Ar group ofFormula I above:

Ar M.P., C. o-Methylphenyl 217 m-Methylphenyl 193 p-Hydroxyphenyl198-200 m-Chlorophenyl 176-178 p-Chlorophenyl 205-207 p-Bromophenyl197-203 p-Fluorophenyl 210-214 2,4-dichlorophenyl 243-2472,4-dichlorophenyl(monoacetate dihydrate 230-233 3,4-dichlorophenyl240-243 m-Methoxyphenyl 186-189 p-Methoxyphenyl 215-2163,4,5-trimethoxyphenyl 201-203 p-Ethoxyphenyl 242-244p-Dimethylaminophenyl 223-225 4-acetaminophenyl 256 Example 14 Example15 2,4 diamino 6-[(2 naphthylmethylene)amino] quinazoline (15.2 g.) inethanol (700 ml.) is hydrogenated at C. and 60 atmospheres of hydrogenpressure for 3 hours using Raney nickel catalyst. The reaction mixtureis filtered while hot and the solid product isolated by addition ofwater (200 ml.) and cooling. The product is 2,4-diamino-6-(2-naphthylmethyl)-amino] quinazoline; M.P. 242 C. In the same manner,starting with equivalent amounts of the corresponding Z-furfurylideneand 2- and 4-pyridylmethylene compounds instead of the above 2-naphthylrnethylene compound, one obtains the corresponding6-[(2-furfuryl)-, 2-pyridylmethyl)-, and (4- pyridylmethyl -amino-2,4-diaminoquinazolines melting respectively at 215-216, 256, and284-288 C. after recrystallization from 50% ethanol. By the sameprocedure in which the Z-naphthylmethylene starting material is replacedby an equivalent amount of the corresponding l-naphthylmethylenestarting material or the 2-methyl-, 2,3-dimethyl-, 2,6-dimethyl-, and4,7-dimethyl-1-naphthylene derivatives thereof (obtained by theprocedure of Example 4 using 2,4,6-triaminoquinazoline and thecorresponding l-naphthylaldehyde), one obtains the following:2,4-diamino-6-[ l-naphthylmethyl) amino] quinazoline 2,4-diamino-6-2-methyl-1-naphthylmethyl) amino]-quinazoline 2,4-diamino-6-[(2,3-dimethyl- 1 -naphthylmethyl) amino] quinazoline 2,4-diamino-6-[(2,6-dimethyl-l-naphthylmethyl) amino] quinazoline 2,4-diamino-6-[(4,7-dimethyll-naphthylmethyl amino]quinazoline Also by the sameprocedure, where the 2-naphthylmethylene starting material is replacedby an equivalent amount of a corresponding halo-, hydroxy-, oralkoxysubstituted naphthylmethylene starting material (obtained bycondensation of the appropriate aldehyde listed below with2,4,6-triaminoquinazoline according to the procedure of Example 16(a)hereinafter), the following products are produced:

Example 16 (a) 2,4,6-triaminoquinazoline (17.5 g.) and 1-nitro-2-naphthaldehyde (20.1 g.) in acetic acid (750 ml.) for 3 hours. Thereaction mixture is cooled and the. product, 2,4 diamino6-[(1-nitro-2-naphthylmethylene)amino] quinazoline, which separates insolid form, is collected by filtration. By replacing the naphthaldehydestarting material with an equivalent amount of p-nitrobenzaldehyde, oneobtains by this procedure 2,4-diamino-6-(pnitrobenzylideneamino)quinazoline.

(b) The naphthylmethylene product of (a) is dissolved indimethylformamide (300 ml.) and the solution treated with a coldsolution of sodium borohydride (11.4 g.) in methanol (150 ml.). Afterone-half hour, the mixture is heated to 80 C. and is allowed to cool.The solid product which separates,2,4-diamino-6-[(1-nitro-2-naphthylmethyl)arnino]-quinazoline, iscollected by filtration and is dried. The corresponding 4-, 5- and8-nitro-1-naphthylmethyl isornct'S are prepared by a procedure which isthe same in all respects to the instant example except that the startingmaterial 1-nitro-2-naphthaldehyde is replaced with an equivalent amountof the corresponding 4-, or 8-nitro-l-naphthaldehyde, respectively;similarly replacement with an equivalent of p-nitrobenzaldehyde providesthe product 2,4-diamino-6-(p-nitrobenzylamino,J quinazoline.

(c) 2,4 diamino 6-[(1-nitro-2-naphthylmethyleneJ- amino]quinazoline (30g.), prepared as in (a) above, is dissolved in dimethylformamide (300ml.) and the solution hydrogenated for six hours at 110 C. under 60atmospheres of hydrogen pressure using Raney nickel catalyst. Themixture is filtered While hot, and the filtrate is concentrated and thendiluted with an equal volume of water. The product which separates,2,4-diamino-6-[(1- amino-2-naphthylmethyl) aminol-quinazoline, iscollected and dried. The corresponding 4-, 5- and8-amino-1-naphthylrnethyl isomers can be prepared by this same procedureusing as a starting material the corresponding 4-, 5- and8-nitro-1-naphthylmethylene isomers obtainable by the procedure ofparagraph (a) starting from 4-, 5- and 8-nitrol-naphthaldehyde,respectively; likewise, where the starting material isp-nitrobenzaldehyde the product obtained by proceeding in accordancewith (a) and (c) is 2.4- diamino-6-(p-aminobenzylamine)quinazoline.

Example 17 (a) A mixture of 3.9 g. of the starting material, 2.4-diamino-6-[(3,4 dichlorobenzyDamino]quinazoline. l.5 g. of methyliodide, 1.5 g. of potassium carbonate and 50 ml. of acetone is stirredand heated at reflux for hours. The mixture is cooled, filtered and thefiltrate evaporated at reduced pressure to give the free base product,2,4-diamino-6-[(3,4-dichlorobenzyl)rnethylaminolquinazoline. To preparea salt such as the hydrochloride, the free base is dissolved in ethanoland the solution treated with one equivalent of hydrochloric acid. Ondilution with water and cooling, the monohydrochloride salt hemihydrateseparates as a crystalline solid; M.P. 289-290 C.

By the same procedure, other benzylmethylamino compounds are preparedusing proportionate amounts of the appropriate benzylaminoquinazolineand alkyl halide, as follows:2,4-diamino-6-(benzylmethylamino)quinazoline monohydrochloridemonohydrate; M.P. 290-292 C. 2,4-diamino-6-[ a-methylbenzyl)methylamino] quinazoline 2,4-diamino-6- (3 ,4-dichloro-a-methylbenzyl)-methylamino] quinazoline.

(b) The starting material for (a) above is prepared by condensingequivalent quantities of 3,4-dichlorobenzaldehyde and2,4,6-triaminoquinazoline in 2-ethoxyethanol and then hydrogenating thereaction mixture with an equal solvent volume of ethanol at hydrogenpressure of 50 atmospheres using Raney nickel catalyst for 2 hours at C.The product is collected from the reaction mixture after addition ofwater and is recrystallized from ethanol; M.P. 240-243 C.

Example 18 A solution of 18.6 g. of the starting material2,4,6-triamino-5-chloroquinazoline and 17.5 g. of3,4-dichlorobenzaldehyde in 200 ml. of ethanol is heated at reflux for 2hours. The solution is cooled and there is added, with stirring, asolution of 9.9 g. of sodium borohydride in ml. of methanol at 0-5 C.After one-half hour, the mixture is heated to boiling, then allowed tocool. The precipitated product, 2,4-diamino 5 chloro 6 [(3,4dichlorobenzyl)amino]quinazoline, is collected and recrystallized fromaqueous ethanol; M.P. 218220 C.

By the same procedure, other related compounds are prepared startingwith equivalent amounts of the appropriate carbonyl compound and thestarting material, as follows:

Carbonyl compound 2,4-diarnino--cl1loroquinazoline compound1-ch1oro2-naphthaldehyde. l-nitro-lnaphthaldehyde.6-Kl-nitro-2-naphthylmethyl)ammo].

6-[ (Z-thienylrnethyl) amino].

Example 19 (a) 2,4-diamino 6 [(Z-naphthylmethyl)amino]quinazoline (31.5g., 0.1 mole) and 4,4-methylenebis(3-hydroxy-2-naphthoic acid) (194 g.,0.05 mole) are dissolved together in hot 96% ethanol with stirring. Thesolution is stirred and heated on a steam bath for about minutes and isthen cooled and allowed to stand, if necessary, until formation of aprecipitate. The desired solid product, 2,4-

diamino 6 [(Z-naphthylmethyl)amino]quinazoline salt with one halfformula weight of 4,4-methylenebis(3-hydroxy-Z-naphthoic acid), iscollected by filtration and dried.

(b) In place of 4,4'-methylenebis(3-hydroxy-2-naphthoic acid) in theforegoing procedure (a), one can use an equivalent amount of a differentacid or salt, forming substance, as follows, to form the correspondingsalts of 2,4-diamino-6-[ (2-naphthylmethyl)amino] quinazoline:

(i) 4,4-benzylidenebis (3-hydroxy-2-naphthoic acid) (ii)2,2'-dihydroxy(l,1'-binaphthalene)-3,3'-dicarboxylic acid (iii)3,1-dihydroxy-4,4'-methylenedi-2-naphthoic acid (iv)3,6'-dihydroxy-4,5-methylenedi-Z-naphthoic acid (v)4,4-methy1enebis[7-bromo-3-hydroxy-2-naphthoic acid] (vi) Fluorescein.

The naphthoic acids of (iii), (iv), and (v) can be prepared in separateprocedures as follows:

(iii) A slurry of 4-(chloromethyl)-3-hydroxy-2-naphthoic acid, methylester g.) in 500 ml. of hot glacial acetic acid is added to a hotsolution of 15 g. of l-hydroxy- 2-naphthoic acid in 250 ml. of glacialacetic acid. The mixture is stirred and heated on a steam bath for 3 to4 hours. Upon cooling, the intermediate product, 3,1-dihydroxy-4,4-methylenedi-Z-naphthoic acid-Z-methyl ester, is collected as a solidby filtration and is washed with glacial acetic acid and dried undervacuum at 75 C.; M.P. 253- 256 C. (dec.). The product is dissolved in ahalf-liter of l N sodium hydroxide solution and the resulting solutionis heated on a steam bath for two hours. The hydrolysis rnixture isfiltered, the filtrate poured into an excess of dilute hydrochloricacid, and the desired acid product(3,1-dihydroxy-4,4-rnethylenedi-2-naphthoic acid) is collected as asolid by filtration. The product, after washing with water, drying andcrystallization from dimethylformamide-water, melts at 255256 C. (dec.).

(iv) Similarly, the corresponding acid isomer,3,6'-dihydroxy-4,5'-rnethylenedi-2-naphthoic acid (MP. 296- 300 C.), isobtained starting, however, from 6-hydroxy-2- naphthoic acid instead ofl-hydroxy-Z-naphthoic acid.

(v) A mixture of 7-bromo-3-hydroxy-2-naphthoic acid (26.7 g.), sodiumhydroxide (6 g.) and water (700 ml.) is heated to 90 C. on a steam bath,and 40% formaldehyde solution (6 ml., 0.075 mole) is added. Theresulting solution is stirred and heated for 2 hours, and the solid 14product which separates on cooling is collected, dissolved in hot water,filtered and the filtrate acidified. The desired acid product whichseparates, 4,4-methylenebis[7-bromo- 3-hydroxy-2-naphthoic acid], iscollected and dried under vacuum; M.P. 330335 C. (dec.).

In place of 2,4-diamino-6-[(Z-naphthylmethyl)amino]- quinazoline in theforegoing procedure (a), one can use an equivalent amount of any one ofthe following quinazolines to form the corresponding quinazoline salt:

2,4-diamino-6- 2,4,6-trimethylbenzylamino) quinazoline 2,4-diamino-6- (3,4-dichlorobenzylamino) quinazoline 2,4-diamino-6- (p-ethoxybenzylaminoquinazoline 2,4-diamino-6- p-chlorobenzylamino quinazoline2,4-diamino-6- o-methylbenzylamino) quinazoline 2,4-diamino-6-(p-methylbenzylamino) quinazoline 2,4-diamino-6-b enzylaminoquinazoline.

Also by the same procedure, any of the last-mentioned quinazolines canbe reacted with any of the salt-forming substances (i) to (vi) to obtainuseful salts. For the purposes of the invention, the quinazoline freebases named in this example and salts thereof are preferred for theirsignificant pharmacological action of the type hereinabove described.

I claim:

1. A member selected from the group consisting of a free base2,4,6-triaminoquinazoline of formula:

2. A compound according to claim 1 which in free base form is2,4,6-triaminoquinazoline.

3. A compound according to claim 1 which in free base form is2,4,6-triamino-5-chloroquinazoline.

4. A compound according to claim 1 which in free base form is2,4,6-triamino-5-methylquinazoline.

and acid addition salts thereof, Where X is a member selected from thegroup consisting of hydrogen, chloro and methyl.

References Cited UNITED STATES PATENTS 1,817,982 8/1931 Hentrich et al.260-2564 2,458,214 1/1949 Souders 260-580 2,541,717 2/1951 Petering260--240 2,888,458 5/1959 Stromberg 260240 FOREIGN PATENTS 935,3811/1963 Great Britain. 750,175 6/1956 Great Britain.

OTHER REFERENCES Billman et al.: J. Org. Chem, vol. 22, pp. 1068-1070(1957).

Lowy et al.: An Introduction to Organic Chemistry, 6th ed., pp. 252253,John Wiley and Sons (1945).

JOHN D. RANDOLPH, Primary Examiner U.S. Cl. X.R. 260-240, 465, 999

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,485,842 Dated D m r 2 3 1969 Inv -(g) John Davoll It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 1, line 9, amend "September 17, 1964" to read September 7, 1964line 23, correct the spelling of "triaminoquinazoline" Column 4, line31, correct the spelling of "clinical".

Column 9, line 64, correct the spelling of "separates".

Column 1 line 27, after "formulaz" add:

\W NH and acid addition salts thereof, where X is a member selected fromthe group consisting of hydrogen, chloro and methyl.

Column 14, delete lines 34 to 43.

SIGNED KN SEALED JUN 3 U 1970 fiEAL Luca:

Edward M. Fletcher. In. WILLIAM E. G YIIER,

Auesting Officer Oomissioner of Patents

